The ability to deliver biologically active compounds in a controlled manner over a period of time is an ongoing challenge. The controlled release delivery of biologically active compounds can improve the bioavailability by protecting them against degradation in vivo and concomitantly replace multiple injections or continuous infusions which are necessary due to the short half-life of these biologically active compounds. Reduced frequency for administration could improve patient compliance. Biodegradable polymers have been used for more than three decades as drug carriers in implantable devices [Langer, R. and Chasin, M. (Eds) Polymers as Drug Delivery Systems, Marcel Dekker, New York, N.Y., 1990]. The advantage of using biodegradable polymers as sustained delivery carriers for biologically active compounds is that they do not require removal after delivering their dose because they are hydrolyzed to soluble non-toxic oligomers or monomers. The biodegradation rate depends on the physicochemical properties of the polymers, including crystallinity, hydrophobicity, chemical structure, molecular weight and molecular weight distribution. Theoretically, these properties can be designed or tailored to develop drug delivery systems in a controlled release manner and desired duration of treatment.
Various biologically active compounds have been described in the prior art in combination with biodegradable polymers to achieve extended release by using appropriate polymers under physiological conditions. The biologically active compound in compositions of the prior art can be in the form of an uncharged molecule, molecular complex, salt, ether, ester, or amide [U.S. Pat. Nos. 6,528,080, 5,739,176, 5,077,049 and 4,938,763]. Specific examples of salts used in injectable or implantable compositions include acetate, chloride, citrate, maleate, phosphate, succinate, sulfate, tartrate, etc. However, the success of such formulations is limited to a few biologically active compounds which are stable and have a wide therapeutic blood concentration range, e.g., leuprolide, gosorelin and rhGH. If a biologically active compound contains reactive functional groups and has a narrow therapeutic blood concentration window, the successful development of controlled release delivery systems for such a biologically active compound has been very challenging. This is primarily due to the instability of the biologically active compounds in the delivery systems and uncontrolled release pattern of the biologically active compounds from the delivery systems, e.g., burst effect at the beginning, in the middle, and at the end of the release. Some biologically active compounds contain basic groups (including primary, secondary, and tertiary amines) may pose serious obstacles for successful development of controlled release delivery systems using biodegradable polymers. The compounds may alter (or catalyze) the hydrolysis process of the polymer carrier in an uncontrolled manner and/or react with the polymers or their degradation products to form undesired amide drug derivatives. The formation of these derivatives not only decreases the dose actually delivered, but also may causes unexpected side effect. The interaction/reaction between biologically active compound and polymer carriers may occur either 1) during formulation when the biologically active compounds are incorporated in the polymer carrier, such as microencapsulation, injection molding, extrusion molding, mixing with polymer solutions in organic solvent, etc.; 2) during storage and 3) during the process of biodegradation and the release of biologically active compounds in vivo.
The interaction/reaction between biologically active compounds contain basic functional groups, i.e., amines, and polymers were reported during the microparticle formation process using solvent evaporation/extraction methods where the biologically active compound and polymer were dissolved/dispersed in organic solvents [Krishnan M. and Flanagan D R., J Control Release. 2000 Nov. 3; 69(2):273-81]. Significant amount of amide moieties were formed. It was clearly shown that commonly used solvents for fabrication of biodegradable polymer drug delivery systems could permit rapid reaction between biologically active compound and polymer. In another study, the accelerated degradation of polymers by organic amines was reported [Lin W J, Flanagan D R, Linhardt R J. Pharm Res. 1994 July; 11(7):1030-4.]. It was also reported that the degradation of polymer matrix containing simple drug salts, e.g., epirubicin HCl, was found to hasten the degradation of the polymers and subsequently affect the release behavior from these particles [Birnbaum D T, Brannon-Peppas L. Molecular weight distribution changes during degradation and release of PLGA nanoparticles containing epirubicin HCl. J Biomater Sci Polym Ed. 2003; 14(1):87-102]. Domb et al reported the drugs containing reactive amines and their salts in the in vitro aqueous degradation media also expedites the degradation of biodegradable polymers [Domb A J, Turovsky L, Nudelman R., Pharm Res. 1994 June; 11(6):865-8]. Both of the reaction and catalyzed degradation are undesirable for the controlled release delivery of biologically active compounds for a prolonged time period.
When biodegradable polymers such as polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polyortho-esters, polyacetals and the like are used as drug delivery systems, the biodegradation of polymers (such as polylactide and polylactide-co-glycolide for example) leads to water-uptake and generation of aqueous channels or pores from which biologically active compounds can leak out (or diffuse out) if they become water soluble. In addition, the accumulation of polymer degradation products lowers pH within the degrading polymer matrices and local pH values between 1.5 and 4.7 have been recently reported (Na D H, Youn Y S, Lee S D, Son M O, Kim W A, DeLuca P P, Lee K C. Monitoring of peptide acylation inside degrading PLGA microspheres by capillary electrophoresis and MALDI-TOF mass spectrometry. J Control Release. 2003 Oct. 30; 92(3):291-9; and references cited therein). The acidic microenvironment inside the polymer matrices can induce several undesired chemical degradation reactions, especially for the biologically active compounds containing reactive amine groups, such as peptides and proteins.
More examples with respect to the instability or reaction/interaction of biologically active compounds and polymers during formulation, storage, and in vivo release in the prior art have been reviewed in the literature, [Schwendeman S P., Recent advances in the stabilization of proteins encapsulated in injectable PLGA delivery systems. Crit Rev Ther Drug Carrier Syst. 2002; 19(1):73-98; Sinha V R, Trehan A., Biodegradable microspheres for protein delivery. J Control Release. 2003 Jul. 31; 90(3):261-80], which are all incorporated herein by reference.
Some organic acids, such as acetic acid, citric acid, benzoic acid, succinic acid, tartaric acid, heparin, ascorbic acid and their non-toxic salts, have been described in the prior art and used in various controlled release biodegradable systems as polymer degradation enhancers. (PCT-patent application WO93/17668 (page 14, lines 4-13) and U.S. Pat. No. 4,675,189) (Column 11, lines 5-19). Thus, such acid additives are not expected to stabilize the polymers.
Various other approaches have been investigated to achieve successful controlled release delivery of biologically active compounds containing reactive basic groups. However, despite tremendous research efforts, there are only a few products for controlled release delivery of biologically active compounds commercially available so far [see e.g., U.S. Pat. No. 4,728,721 (Leuprolide, Lupron Depot); U.S. Pat. No. 4,938,763 (Leuprolide, Eligard); U.S. Pat. No. 5,225,205 (Triptorelin Pamoate, Trelstar); U.S. Pat. No. 4,767,628 (Goserelin Acetate, Zoladex); U.S. Pat. No. 5,538,739 (Octreotide, SANDOSTATIN LAR); U.S. Pat. No. 5,654,010 (recombinant human growth hormone, Nutropin Depot); U.S. Pat. Nos. 4,675,189; 5,480,656; 4,728,721].
Clearly, there is a need to develop novel and suitable delivery system which stabilizes the biologically active compounds, controls the degradation of polymers, limits the burst effect, and maintains drug release within therapeutic limits for the duration of the treatment. Thus, it is an object of this invention to address the above-enumerated deficiencies in the prior art and provide a pharmaceutical composition for controlled release delivery of biologically active compounds to a subject comprising:                a) a complex of a biologically active compound having at least one basic functional group and a polyanion derived from hexahydroxycyclohexane having at least two negatively charged functional groups; and        b) a pharmaceutically acceptable carrier comprising a biodegradable, water-insoluble polymer.        
The instant invention also provides methods for producing such controlled release pharmaceutical compositions and methods of use thereof.